PL216059B1 - Colon cleansing compositions - Google Patents

Abstract

Disclosed are compositions comprising, per litre of aqueous solution, from 30 to 350 g polyethylene glycol, from 3 to 20g of an ascorbic acid component comprising a mixture of ascorbic acid and one or more salts of ascorbic acid, and optionally one or more electrolytes selected from sodium chloride, potassium chloride, sodium hydrogen carbonate and one or more alkali metal or alkaline earth metal sulfates. Solutions and kits containing said components are also disclosed.

Description

The invention relates to a dry composition for mixing with water, a kit containing dry composition ingredients, an aqueous solution of the dry composition, and the use of the dry composition in the manufacture of a medicament for cleansing the colon of a mammal.

Colon cleansing is performed prior to a number of diagnostic and surgical procedures, e.g., colonoscopy, contrast rectal infusion, or colon surgery. It is also used to prevent infections following lower gastrointestinal surgery. Colon cleansing is also known as emptying.

Various methods are known for cleansing the colon. Corresponding dietary modification, laxatives, laxatives and enemas have traditionally been used (Thomas, G. et al., Gastroenterology, 1982, 82, 435-437). Sodium phosphate solutions (Clarkston, WK et al., Gastrointestinal Endoscopy, 1996, 43, 43-48) and magnesium citrate / sodium picosulfate solutions are also used (Regev, A. et al., Am. J. Gastroenterol., 1998, 93, 1478-1482).

The methods mentioned have various disadvantages. Changing the diet and applying laxatives is time consuming; enemas are unpleasant for the patient; and after the use of laxatives, enemas and sodium phosphate solutions, loss of salt and water that is hazardous to health may occur.

Sodium phosphate solutions, such as that available from C.B. Fleet Company Inc. (4615 Murray Place,

PO Box 11349, Lynchburg, Virginia 24506, USA) under the trade name Phospho-soda® are hyperosmotic solutions that increase water retention in the intestines, thereby supporting the peristaltic movement of the intestines. Phospho-soda contains, per 5 ml, 2.4 g of monobasic sodium phosphate monohydrate with 0.9 g of sodium phosphate dibasic heptahydrate in a buffered aqueous solution. Typically an adult patient is given 20 to 45 ml, followed by a copious amount of water to drink. If the patient does not drink water, elevated plasma levels of sodium and phosphate can lead to serious kidney problems. The risk of these side effects necessitates direct medical supervision while administering Phospho-soda.

Another approach to colon cleansing involves orthostatic bowel lavage, in which the patient is administered a large volume of electrolyte solution, either to be drunk or infused through a nasogastric tube. Such lavage solutions are also known as intestinal lavage solutions. Ingestion of the solution leads to diarrhea and therefore cleansing of the colon. This method is generally faster than traditional solutions. Previously, sodium chloride was the main ingredient in rinsing solutions. However, absorption into the bloodstream of a patient's intestine of a significant amount of such saline-based lavage solutions causes a rapid increase in intravascular volume, resulting in severe complications in some patients.

In 1980, Davis et al. developed a washing solution with minimal absorption or secretion of water and electrolytes (Davis G.R. et al., Gastroenterology, 1980, 78, 991-995). The solution contained sodium sulfate and polyethylene glycol. Sulfate ions are poorly absorbed in the intestine. As a result, sodium absorption is significantly reduced when the predominant counter-anion present in the lavage solution in the intestine is sulfate and not chloride or bicarbonate. In addition to sodium sulfate (40.0 mM, 5.68 g / L), the solution described by Davis et al. contained sodium chloride (25 mM, 1.463 g / l), potassium chloride (10 mM, 0.745 g / l), sodium bicarbonate (20 mM, 1.680 g / l), polyethylene glycol (PEG 4000 carbonate, 64 g / l) and water. The solution was administered in the amount of 4 liters. The solution has been shown to be effective in cleansing the gastrointestinal tract and is now commercially available under the name GoLYTELY® (Braintree Laboratories Inc, Braintree, Massachusetts, U.S.A.). The commercially available GoLYTELY composition, also known as Klean Prep®, available from August 1996 and at the time of this application, is a dry powder containing sodium sulfate (40.0 mM, 5.685 g / l), sodium chloride (25 mM, 1.464 g / l), potassium chloride (10 mM, 0.743 g / l), sodium bicarbonate (20 mM, 1.685 g / l) and PEG 3350 polyethylene glycol (59 g / l) for application to 4 liters with water. GoLYTELY is also available as an aqueous solution.

The GoLYTELY solution, while effective, has a very salty taste that is difficult for the patient to accept. Typically the composition is in the form of an aqueous solution of four or more liters, and it is essential that the patient ingest the entire recommended volume. Taking such a large volume at once is also difficult for the patient to accept.

PL 216 059 B1

Fordtran et al. (WO 87/00754) then developed a reduced sodium sulphate solution (RSS) containing a relatively large amount of polyethylene glycol (75 to 300 g / l) instead of sodium sulphate. A preferred solution, disclosed in international application WO 87/00754, comprises PEG 3350 (120 g / l), sodium bicarbonate (1.68 g / l), potassium chloride (0.74 g / l) and sodium chloride (1.46 g / l) and is also administered in the amount of 4 liters. A solution very similar to the preferred solution of International Application WO 87/00754 is sold by Braintree Laboratories Inc (Braintree, Massachusetts, U.S.A.) under the name NuLYTELY® (also initially under the name GoLYTELY-RSS). NuLYTELY is composed of PEG 3350 (105 g / l), sodium bicarbonate (1.43 g / l), potassium chloride (0.37 g / l) and sodium chloride (2.80 g / l) and is in the form of dry powder to be spread with water to a volume of 4 liters.

GoLYTELY and NuLYTELY solutions, while effective in cleansing the colon in a clinical setting, should be administered in large amounts, typically four liters. The ingestion of such a volume of bowel lavage solution is generally unpleasant or even impossible for many patients, may lead to gag reflexes and is time consuming. Despite the lack of sodium sulfate in NuLYTELY, both NuLYTELY and GoLYTELY have an unpleasant salty taste. The unpleasant taste exacerbates the problem of patient discipline, especially when the patient is not under medical supervision.

International application WO 89/05659 (Borody) discloses an orthostatic washing solution containing polyethylene glycol, electrolytes and from 0.25 to 50 g / l ascorbic acid (vitamin C) or a salt thereof. The presence of ascorbic acid or its salts is intended to reduce the required volume of the solution to 3 liters or less. While about 3 g of ascorbic acid can be adsorbed in the intestines (Hornig, D. et al., Int. J. Vit. Nutr. Res., 1980, 50, 309), an excess amount of ascorbic acid as described in the international application WO 89/05659, causes diarrhea and inhibits the formation of bacterial gas and the multiplication of bacteria. Ascorbic acid has also been found to facilitate the ingestion of the rinse solution since its pleasant acidic taste masks the usually nauseating salty taste of the polyethylene glycol solution.

Patent application EP0436061 describes an intestinal lavage composition which comprises at least one water-soluble polymer polyethylene glycol, dextran, dextrin, hydroxyethyl starch, polydextrose, acacia, pullulan and pectin; organic acid sodium salt; an organic acid potassium salt; sodium chloride; potassium chloride and sodium sulfate, and is described by a specific formula wherein the total potassium ion content of the composition is in the range of 2 to 12 mEq. The intestinal lavage composition is in the form of an easy to prepare enteral solution, easy for patients to take, with limited water absorption, has no effect on the electrolyte balance in the living organism with a very good cleansing effect, does not contain bicarbonate ions, and is therefore pharmaceutically stable and can be stored for a long time.

The solutions described by Borody contain polyethylene glycol (preferably PEG 3350 or PEG 4000) at a concentration of 30-60 g / liter together with inorganic electrolytes (sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate). In any specified solution, the amount

The PEG is adjusted so that the osmolarity of the solution is approximately 289 mOsmol / L (i.e. the solution is isotonic). The osmolarity of a solution can be measured using standard laboratory techniques. The osmolarity can also be calculated by knowing the components of the solution. Details on the calculation of osmolarity are given later in the description.

The formulation described by Borody has been commercially available in Australia for over 10 years under the trademark GLYCOPREP C (Pharmatel). The dry composition of GLYCOPREP C contains PEG 3350 (53 g / l), sodium chloride (2.63 g / l), potassium chloride (0.743 g / l), sodium sulfate (5.6 g / l), ascorbic acid (6 g / l), aspartame (0.360 g / l), citric acid (0.900 g / l) and lemon flavor (0.090 g / l). Generally 3 liters of solution are administered.

While the addition of ascorbic acid improves the enteric formulation to some extent, this formulation should nevertheless be administered in an amount of approximately 3 liters. The ingestion of this volume of bowel lavage solution is still usually unpleasant or, for some patients, even impossible, may lead to retching and is time consuming. Accordingly, there is still a need for more palatable lavage solutions that are effective when administered in a smaller volume.

Colon cleansing is performed prior to many surgical or diagnostic procedures including colonoscopy, contrast rectal enema, sigmoid colonoscopy, and colon surgery. It is desirable that the colon cleansing procedure be performed by the patient

The procedure should be performed independently, without medical supervision, at home, before arriving at the hospital or before an elective surgery, i.e. surgical or diagnostic. It is important to discipline the patient without medical supervision in order to achieve a satisfactory degree of colon cleansing.

The compositions known in the art are listed in Table 1. In this table the amounts indicated correspond to amounts per liter of aqueous solution. The table also shows the calculated osmolarity of the solutions (in mOsmoles / L) together with the recommended dose (in liters).

T a b l i c a 1:

Known colon cleansing compositions

Preparation PEG g Na2SO4 g NaHCOa g NaCl g KCl g Vit C g Osmium Volume AND GoLYTELY 60 5.7 1.93 1.46 0.75 - 255 4 NuLYTELY 105 - 1.43 2.8 0.37 - 176 4 Glycoprep C 53 5.6 - 2.63 0.74 6.0 291 3

It has now surprisingly been found that a cleansing solution containing an alkali metal or alkaline earth metal sulfate, ascorbic acid and / or one or more of its salts, a relatively large amount of PEG and, optionally, additional electrolytes, has an effective cleansing effect when administered in a small volume and is pleasant. in taste. The cleansing solution containing the composition of the invention provides a satisfactory cleansing of the colon after use in an amount of approximately 2 liters. Typical cleansing solutions need to be administered in an amount of at least 3 to 4 liters.

PEG is known to contribute to the development of diarrhea by increasing the poor absorption of electrolytes. However, it has now surprisingly been found that a cleansing solution which contains an alkali metal or alkaline earth metal sulfate, ascorbic acid and / or one or more of its salts, a relatively large amount of PEG and, optionally, additional electrolytes, has a strong cleansing or laxative effect. Thus, it has been found that a smaller volume of this solution is sufficient and the solution remains pleasant to the taste. The cleansing solution provides a satisfactory cleansing of the colon, e.g. for colonoscopy, when used in an amount of approximately 2 liters.

The invention relates to a dry composition for mixing with water, characterized in that it contains the following ingredients per liter of aqueous solution of the composition:

a) 80 to 150 g of polyethylene glycol (PEG),

b) 3 to 20 g of ascorbic acid, one or more salts of ascorbic acid or a mixture of ascorbic acid and one or more salts of ascorbic acid,

c) 1 to 15 g of alkali metal or alkaline earth metal sulphate or a mixture of alkali metal sulphates or alkaline earth metal sulphates and

d) optionally, one or more electrolytes selected from the group consisting of sodium chloride, potassium chloride and sodium bicarbonate, wherein the components of the composition are selected such that 1 liter of prepared aqueous solution of the composition has an osmolarity in the range of 300 to 700 mOsmol / L (300 to 700 mol m ^-3 ).

Preferably, the aqueous solution has an osmolarity of 330 mOsmol / L (300 mol m ^-3 ) or higher.

Preferably, the aqueous solution has an osmolarity in the range of 550 mOsmol / L (550 mol m ^-3 ) or less.

Preferably, the polyethylene glycol has an average molecular weight of 2,000 daltons or more.

Preferably, the polyethylene glycol has an average molecular weight of 4500 or less.

Preferably, the polyethylene glycol has an average molecular weight of 3350 or 4000.

Preferably the composition comprises 90 g or more of polyethylene glycol (PEG) per liter.

Preferably the composition comprises 125 g or less of polyethylene glycol (PEG) per liter.

Preferably the composition comprises 100 g polyethylene glycol (PEG) per liter.

Preferably the composition comprises an alkali metal or alkaline earth metal sulphate or a mixture of alkali metal or alkaline earth metal sulphates in an amount of 3 g or more per liter.

Preferably the composition comprises an alkali metal or alkaline earth metal sulphate or a mixture of alkali metal or alkaline earth metal sulphates in an amount of 9 g or less per liter.

PL 216 059 B1

Preferably the composition comprises an alkali metal or alkaline earth metal sulphate or a mixture of an alkali metal or alkaline earth metal sulphate in an amount of 7.5 g per liter.

Preferably, the alkali metal or alkaline earth metal is magnesium. when the alkali metal or alkaline earth metal is sodium. when the composition contains sodium chloride.

when the composition contains sodium chloride in an amount of 2 g or more per liter. when the composition contains potassium chloride. when the composition comprises potassium chloride in an amount of 0.5 g or more per liter. when the composition comprises ascorbic acid or its salt in an amount of 5 g or more per liter. where the composition comprises ascorbic acid or a salt thereof in an amount of 15 g or less per liter. when the composition comprises ascorbic acid and a salt thereof. when the composition comprises ascorbic acid and its salt in a weight ratio in preferably,

Preferably,

Preferably,

Preferably,

Preferably,

Preferably,

Preferably,

Preferably,

Preferably, the range is from 1: 9 to 9: 1.

Preferably the composition comprises ascorbic acid and its salt in a weight ratio ranging from 2: 8 to 8: 2.

Preferably the composition comprises ascorbic acid and its salt in a weight ratio ranging from 3: 7 to 7: 3.

Preferably the composition comprises ascorbic acid and its salt in a weight ratio ranging from 4: 6 to 6: 4.

Preferably, the ascorbic acid salt is an alkali metal salt or an alkaline earth metal salt.

Preferably, the salt of ascorbic acid is selected from the group consisting of sodium ascorbate, potassium ascorbate, magnesium ascorbate and calcium ascorbate.

Preferably the composition comprises sodium ascorbate.

Preferably the composition further comprises a flavor.

Preferably, the composition comprises a lemon flavor as the flavor.

Preferably, the composition further comprises a sweetener which is not a substrate for the gut bacteria.

Preferably the sweetener is selected from the group consisting of aspartame, acesulfame K, saccharin or a mixture thereof.

Preferably citric acid is present.

Preferably, the ascorbic acid and / or the salt of ascorbic acid are coated.

Preferably, per liter of the aqueous solution prepared therefrom, it contains 90 to 125 g of polyethylene glycol PEG 3350 or PEG 4000.

Preferably, per liter of the aqueous solution prepared therefrom, it contains 5 to 15 g of an ascorbate component containing ascorbic acid and sodium ascorbate in a weight ratio of 3: 7 to 7: 3.

Preferably, 5 to 10 g of sodium sulphate are present per liter of aqueous solution prepared therefrom.

Preferably, it contains 2 to 4 g of sodium chloride per liter of aqueous solution prepared therefrom. Preferably, it contains 0.7 to 1.3 g of potassium chloride per liter of an aqueous solution prepared therefrom.

Preferably, it contains two sachets with the following composition:

Sachet 1

PEG 3350 polyethylene glycol 100,000 g Sodium sulfate 7,500 g Sodium chloride 2.691 g Potassium chloride 1.015 g Aspartame 0.233 g Acesulfame K. 0.117 g Lemon flavor 0.340 g

PL 216 059 B1

Sachet 2

Ascorbic acid 4.700 g Sodium ascorbate 5.900 g

Preferably the composition is in a sachet.

Another object of the invention is a dry composition comprising 2 portions, characterized in that the first amount is a composition as defined above for the preparation of a first colon cleansing solution containing polyethylene glycol (PEG), and the second amount is a composition as defined above for the preparation of a second colon cleansing solution containing polyethylene glycol (PEG).

Another object of the invention is a kit containing dry composition ingredients as defined above, characterized in that it comprises at least two parts, wherein the ascorbic acid and / or its salts are packed in the first part and the remaining ingredients are packed in the second part.

Another object of the invention is an aqueous solution of a dry composition as defined above.

Preferably, the solution is used to cleanse the colon of a mammal.

Preferably it is used as a colon cleansing solution.

Preferably the solution is administered orally.

Another object of the invention is the use of a dry composition or solution as defined above in the manufacture of a medicament for cleansing the colon of a mammal.

A cleansing solution comprising an aqueous solution of the dry composition according to the invention, which contains the above-mentioned ingredients in the amounts indicated above, with an osmolarity in the above-specified range and a volume of 0.5 I to 5 L.

The solutions according to the invention are non-isotonic, i.e. they do not have the same osmotic pressure as blood in the intestinal vascular system. These solutions, however, are approximately iso-osmolar, meaning that the solution expelled by the patient has substantially the same ion content as the ingested solution. Consequently, there is no significant change in the net value of the patient's blood ion level.

The osmolarity of a solution is the number of undivided particles dissolved in a solution. For a substance that remains fully associated as a unit in solution (e.g., a neutral organic molecule), the osmolarity and molarity of the solution are essentially the same. For a substance that dissociates as it dissolves (e.g., an ionic salt), osmolarity is the number of moles of discrete dissolved units in solution after dissolution.

Solution osmolarity can be measured using standard laboratory techniques. It can also be calculated knowing the components of the solution. For example, the osmolarity of the GoLytely solution can be calculated as follows:

PEG: 60 g, MW = 3350, one unit per mole in solution:

Share = 60/3350 * 1 = 18.0 mOsmol / l

Na2SO4: 5.7 g, MW = 142, three units per mole in solution:

Share = 5.7 / 142 * 3 = 120.4 mOsmol / l

NaHCO3: 1.93 g, MW = 84, two units per mole in solution:

Share = 1.93 / 84 * 2 = 46.0 mOsmol / l

NaCl: 1.46 g, MW = 58.5, two units per mole in the solution:

Share = 1.46 / 58.5 * 2 = 50.0 mOsmol / l

KCl: 0.75 g, MW = 74.5, two units per mole in solution:

Share = 0.75 / 74.5 * 2 = 20.1 mOsmol

Total osmolarity = 255 mOsmol / l

In some cases, the calculated osmolarity does not equal the measured osmolarity. There are various possible reasons for this, mostly due to the fact that the number of free units dissolved in the solution is not exactly what it would be in an ideal situation. For example, if several components are present, they may form agglomerates resulting in fewer independent dissolved units than calculated. Moreover, as a further example, depending on the pH of the solution, the organic acids and bases may be incompletely dissociated or associated.

A cleansing solution containing more than 100 g / l of PEG (NuLYTELY) has already been described above. It is generally accepted that the cleansing solutions must be isotonic, i.e., of the same

Osmolarity as body fluid in the intestines. Thus, a large amount of PEG is accompanied by a small amount of electrolyte salts to make the cleansing solution isotonic. For example, NuLYTELY solution does not contain sodium sulphate. It has now surprisingly been found that it is not necessary for the cleansing solution to be isotonic and furthermore that a hypertonic solution containing PEG, alkali metal or alkaline earth metal sulfate, or a mixture of alkali metal or alkaline earth metal sulfates, electrolytes and ascorbic acid and / or one or more of its salts are a more effective cleansing solution than isotonic solutions known in the art.

In healthy volunteers, after the administration of a volume of 2 liters, it was found that the hypertonic cleansing solution of the present invention causes a 50% increase in the weight and volume of stool excreted compared to an isotonic solution containing no sodium sulphate and ascorbic acid, but with the same composition. i.e. with the same concentrations of PEG, sodium bicarbonate, sodium chloride and potassium chloride. No side effects were observed. It has also been found that the inventive hypertonic cleansing solution is more effective when administered in the same volume as prior art compositions which are isotonic and contain less sodium sulfate.

Preferably the osmolarity of the cleaning solution of the present invention is 330 mOsmol / L or greater, more preferably 350 mOsmol / L or greater, even more preferably 400 mOsmol / L or greater, e.g. 460 mOsmol / L or greater. Preferably, the osmolarity of the cleaning solution of the present invention is 600 mOsmol / L or less, more preferably 550 mOsmol / L or less, even more preferably 500 mOsmol / L or less, e.g. 470 mOsmol / L or less. For example, the osmolarity can be in a range where the lower limit is selected from 330, 350, 400, and 460 mOsmol / L, and the upper limit is independently selected from 600, 550, 500, and 470 mOsmol / L.

Whilst it has hitherto been thought necessary for the cleansing solution to be isoosmolar and a number of steps have been taken to make it isoosmolar, it has now surprisingly been found that high osmolarity solutions are not only safe but more effective than prior art solutions and that as the volume of fluid ingested is reduced, the likelihood of vomiting is reduced. While the osmolarity value is mainly dependent on polyethylene glycol (PEG), the dual effect of high PEG concentration and increased osmolarity makes the cleansing solution work faster with even greater safety due to reduced side effects. Measurements of the volume of the eluate obtained show that the combination of these two effects is synergistic.

The polyethylene glycol (PEG) used in the composition of the present invention preferably has an average molecular weight of 2,000 or greater. Preferably the PEG has an average molecular weight of 2500 or greater. Preferably the PEG has an average molecular weight of 4,500 or less. For example, PEG 3350 or PEG 4000 may be used as the PEG. Optionally, the PEG used in the composition of the invention may include two or more different types of PEG. The composition of the invention preferably contains 90 g or more of PEG per liter, more preferably 100 g or more of PEG per liter. Preferably, the composition of the invention contains 250 g or less of PEG per liter, more preferably 150 g or less of PEG per liter, even more preferably 140 g or less of PEG per liter, or even 125 g or less of PEG per liter. For example, the composition of the present invention may contain PEG in an amount in the range where the lower limit is 90 or 100 g per liter and the upper limit is independently 350, 250, 150 or 125 g per liter. The composition of the invention may e.g. contain 100 or 125 g of PEG per liter. Most preferably, the composition of the invention contains 100 g PEG per liter.

Preferably, the alkali metal or alkaline earth metal sulfate or mixture of alkali metal or alkaline earth metal sulfates is present in the cleansing composition of the invention in an amount of 2 g or more per liter, more preferably in an amount of 3 g or more per liter, even more preferably in an amount of 5 g or more per liter. Preferably, the alkali metal or alkaline earth metal sulfate or mixture of alkali metal or alkaline earth metal sulfates is present in the cleaning compositions of the invention in an amount of 10 g or less per liter, more preferably in an amount of 9 g or less per liter, even more preferably in an amount of 7.5 g or less per liter. For example, an alkali metal or alkaline earth metal sulfate, or a mixture of alkali metal or alkaline earth metal sulfates, may be present in an amount in a range where the lower limit is selected from 2, 3, and 5 g per liter and the upper limit is independently selected, among 10, 9 and 7.5 g per liter. For example, an alkali metal or alkaline earth metal sulfate or a mixture of alkali metal or alkaline earth metal sulfates is present in an amount of 5 g or 7.5 g per liter, most preferably 7.5 g per liter.

PL 216 059 B1

The alkali or alkaline earth metal can be, for example, sodium, magnesium or calcium. Sodium is generally preferred, but magnesium or calcium can also be used.

The composition according to the invention preferably comprises sodium chloride. Sodium chloride is preferably present in an amount of 0.5 g or more per liter, more preferably 1 g or more per liter, even more preferably in an amount of 2 g or more per liter. Sodium chloride is preferably present in an amount of 7 g or less per liter, more preferably 5 g or less per liter, even more preferably in an amount of 4 g or less per liter. For example, sodium chloride may be present in an amount in a range where the lower limit is selected from 0.5, 1, and 2 g per liter, and the upper limit is independently selected from 7, 5, and 4 g per liter.

The composition according to the invention preferably comprises potassium chloride. Preferably, potassium chloride is present in an amount of 0.2 g or more per liter, more preferably in an amount of 0.5 g or more per liter, most preferably in an amount of 0.7 g or more per liter. Preferably, potassium chloride is present in an amount of 4 g or less per liter, more preferably in an amount of 2 g or less per liter, most preferably in an amount of 1.3 g or less per liter. For example, potassium chloride can be present in an amount in a range where the lower limit is selected from 0.2, 0.5, and 0.7 g per liter and the upper limit is independently selected from 4, 2, and 1.3. g per liter.

The composition according to the invention may contain sodium bicarbonate. When water is added to a composition containing ascorbic acid and bicarbonate, the bicarbonate ions generally degrade with the formation of CO 2 from the reaction between sodium bicarbonate and acids. The same reaction can occur in a dry powder composition if it contains small amounts of moisture, e.g. from ambient moisture. The reaction between the bicarbonate and ascorbic acid in the dry powder composition can be prevented if coated ascorbic acid is used. The reaction can also be prevented by packing the dry composition in two separate containers so that the bicarbonate and ascorbic acid do not come into contact with each other.

The term "ascorbic acid source" as used herein in reference to the compositions of the present invention includes ascorbic acid, one or more of its salts, or a mixture of ascorbic acid and one or more of its salts. The source of ascorbic acid is present in the composition of the invention in an amount of from 3-20 g per liter of solution. Preferably the source of ascorbic acid is present in an amount of 4 g or more per liter, more preferably in an amount of 5 g or more per liter. Preferably the ascorbic acid source is present in an amount of 15 g or less per liter, more preferably in an amount of 10 g or less per liter. For example, the source of ascorbic acid can be present in an amount in the range where the lower limit is 4 or 5 g per liter and the upper limit is independently 15 or 10 g per liter. For example, the source of ascorbic acid is 5 to 10 g per liter, e.g. 5 or 10 g per liter.

Preferred ascorbic acid salts include alkali metal and alkaline earth metal salts, e.g., sodium ascorbate, potassium ascorbate, magnesium ascorbate and calcium ascorbate. A particularly preferred salt of ascorbic acid is sodium ascorbate. Preferably, the source of ascorbic acid comprises both ascorbic acid and one or more of its salts. Preferably, ascorbic acid and its salt (s) are present in a weight ratio ranging from 1: 9 to 9: 1. Ascorbic acid and its salts can, in practice, be used as hydrates. If a hydrate is used, the weight and / or weight ratio mentioned herein corresponds to the weight and / or weight ratio of ascorbic acid or its salt without water of hydration. Preferably ascorbic acid and its salt (s) are present in a weight ratio ranging from 2: 8 to 8: 2, more preferably 3: 7 to 7: 3, even more preferably 4: 6 to 6: 4, e.g. 4.7 to 5 , 9.

It is known that the plasma bicarbonate level can decrease with 0.9% saline or 7.2% mannitol cleansing solutions without a balancing amount of bicarbonate. Decreased plasma bicarbonate levels can have serious undesirable clinical consequences related to decreased blood pH (acidosis) and the consequent decreased CO2 transport efficiency in the bloodstream. Acidosis can lead to weakness, confusion, coma and eventually death. However, it has now been found that the reduction of the plasma bicarbonate level is more marked by the use of a composition containing both ascorbic acid and one or more of its salts. The presence of ascorbate increases the osmotic load of the solution and also helps to maintain the proper level of bicarbonate. This is a further advantage of the compositions of the present invention.

The compositions according to the invention are preferably flavored. The flavor for use in the compositions of the invention should preferably mask the salty taste, be relatively, but not excessively sweet, and be stable in the composition. The flavor gives the solutions a more pleasant taste and therefore increases patient compliance. Preferred flavors include lemon flavor e.g. Ungerer Lemon (available from Ungerer Limited, Sealand Road, Chester, England CH1 4LP), strawberry e.g. Ungerer Strawberry, grapefruit e.g. Ungerer GraPL 216 059 B1 pefruit Flavoring Powder, black currant e.g. Ungerer Blackcurrant, pineapple e.g. IFF (International Flavors and Fragrances) Pineapple Flavoring Powder and vanilla / lemon with lime e.g. IFF Vanilla and Givaudin Roure Lemon and Limona Flav-o-lok. These and other suitable flavors are available from International Flavors and Fragrances Inc. (Duddery Hill, Haverhill, Suffolk, CB9 8LG, England), Ungerer & Company (Sealand Road, Chester, England CH1 4LP) or Firmenich (Firmenich UK Ltd., Hayes Road, Southall, Middlesex UB2 5NN). Preferred flavors include lemon, kiwi, strawberry, and grapefruit. The most preferred flavor is lemon flavor.

Preferred compositions of the invention contain a sweetener. Sugar-based sweeteners are not suitable because they overload the colon with unabsorbed sugars that feed the bacteria. These sugars can be metabolized by bacteria to form explosive gases such as hydrogen and methane. The presence of explosive gases in the colon can be very dangerous if an electrical device is used during colonoscopy or other procedures. Preferred sweeteners include aspartame, acesulfame K, and saccharin, or combinations thereof. Citric acid can also exist as a flavor enhancer.

The ascorbic acid and / or ascorbic acid salt (s) in the dry composition of the present invention may be coated. The coating helps to maintain the stability of the ascorbic acid and / or its salts. As indicated above, ascorbic acid and its salts have a reduced stability in the presence of moisture.

The dry composition according to the invention may be in the form of a powder, granules or any other suitable physical form. The dry composition of the invention may be formulated in a unit dosage form, e.g. in a sachet. Preferably the dry composition is in the form of two or more components, the ascorbic acid and / or its salt (s) being packaged separately from the rest of the components. For example, the first component, e.g. in unit dosage form, e.g. in a sachet, may contain polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, sweeteners and flavors, and the second component, e.g. in unit dosage form, e.g. sachet will then contain ascorbic acid and sodium ascorbate.

The composition according to the invention may be in the form of an aqueous solution, e.g. in one or more containers each containing e.g. 0.5 or 1 liter of solution.

The volume of fluid administered was 1.5 to 3 liters for an adult human and proportionally more or less for a non-adult human mammal.

The exact amount of the solution of the invention to be administered will depend on the patient to be treated. For example, a smaller volume of the cleansing solution is appropriate for administration to young children, and a larger volume of the cleansing solution is appropriate for administration to patients with a prolonged colon transit time.

Colon cleansing may be performed prior to a diagnostic, therapeutic, or surgical procedure being performed on the colon, rectum or anus, or other abdominal area. The diagnostic or surgical procedure may include, for example, colonoscopy, contrast rectal enema, sigmoid colonoscopy, or colon surgery. They can also be used in the treatment of acute gastrointestinal infections, e.g. bacterial or viral gastroenteritis. The goal of such treatment is to remove stools from the infected colon so as to reduce the absorption of toxins and shorten the duration of diarrhea, toxicity, anorexia, nausea, or vomiting. The use of a laxative product after the onset of diarrhea, cramps and malaise allows the removal of the residual, infected part of the intestinal flora from the intestine, thus shortening the duration of the infection.

Preferably, the entire volume of the solution is administered over a period of 1 to 4 hours. This may take place over 1 to 4 hours continuously or periodically. During batch administration, a portion of the solution, typically approximately half, may be administered in the evening prior to diagnostic, therapeutic, or surgical treatment, and the remainder on the day of surgery.

The composition for use according to the invention has the advantageous features of the composition according to the invention as described above.

It has been surprisingly found that a colon cleansing solution containing ascorbic acid and one or more salts of ascorbic acid exhibits less side effects than a cleansing solution containing ascorbic acid without its salts.

In addition, a colon cleansing solution containing ascorbic acid and one or more salts of ascorbic acid has been found to have an even more effective colon cleansing effect than

A solution containing ascorbic acid without its salt. Cleansing solutions containing ascorbic acid salt without ascorbic acid have also been found to be less effective than cleansing solutions containing both ascorbic acid and one or more of its salts.

Plasma levels of bicarbonate and other anions may drop when using ascorbic acid-only cleansing solutions. The presence of one or more salts of ascorbic acid contributes to the osmotic loading of the solution and also helps to maintain an appropriate level of bicarbonate in the plasma. The decrease in plasma bicarbonate levels is much less by using a composition containing both ascorbic acid and one or more of its salts.

Any suitable salt of ascorbic acid can be used. Preferred ascorbic acid salts include alkali metal and alkaline earth metal salts, e.g., sodium ascorbate, potassium ascorbate, magnesium ascorbate and calcium ascorbate. A particularly preferred salt of ascorbic acid is sodium ascorbate. Preferably this salt is sodium ascorbate.

Preferably, ascorbic acid and its salt (s) are present in a weight ratio ranging from 1: 9 to 9: 1. Ascorbic acid or its salts can in practice be hydrated. If a hydrate is used, the weight and / or weight ratio mentioned herein corresponds to the weight and / or weight ratio of ascorbic acid and its salt without water of hydration. Preferably ascorbic acid and its salt are present in a weight ratio in the range 2: 8 to 8: 2, more preferably 3: 7 to 7: 3, even more preferably 4: 6 to 6: 4, e.g. 4.7: 5.9.

The composition of the invention comprising ascorbic acid and one or more of its salts preferably further comprises one or more electrolytes selected from the group consisting of sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. The composition according to the invention preferably comprises sodium sulfate.

The composition according to the invention as described above may take the form of an aqueous solution or a dry composition for solution preparation. In such a dry preparation, the ascorbic acid and / or the ascorbic acid salt (s) may be coated. Such a coating helps to preserve the stability of ascorbic acid or its salt. Ascorbic acid and its salts have a reduced stability in the presence of moisture.

The dry composition may be in unit dosage form, for example, in a sachet. The dry composition may be in the form of two or more components, the ascorbic acid and / or its salt (s) being packaged separately from the rest of the components. For example, the first unit dosage form, e.g., the first sachet, may contain polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, sweeteners and flavors, and the second unit dosage form, e.g., the second sachet, may contain ascorbic acid and sodium ascorbate.

The present invention further relates to a method of cleansing the colon of a mammal, comprising orally administering to the mammal a formulation comprising, per liter, the following ingredients:

- 30 to 350 g of polyethylene glycol,

- 3 to 20 g of a mixture of ascorbic acid and salts of ascorbic acid,

- optionally, one or more electrolytes selected from the group consisting of sodium chloride, potassium chloride, sodium bicarbonate and alkali metal or alkaline earth metal sulphates, the volume of the composition administered is from 1.5 to 4 liters for an adult human and proportionally more or less for a non-mammalian mammal. adult man. The exact amount of solution to be administered will depend on the patient to be treated. For example, a lower dose of the cleansing solution is appropriate for the treatment of young children and a larger dose of the cleansing solution is appropriate for administration to patients with a prolonged colon transit time.

The method of the present invention can be used to clean the colon prior to performing diagnostic, therapeutic or surgical treatment of the colon, rectum or anus, or other abdominal part. The diagnostic or surgical procedure may be, for example, colonoscopy, contrast rectal enema, sigmoid colonoscopy, or colon surgery. The method of the present invention may also be used in the treatment of acute gastrointestinal infections, e.g. bacterial or viral gastroenteritis.

Preferably, the entire volume of fluid is administered over a period of 1 to 4 hours. This may take place over 1 to 4 hours continuously or periodically. In one mode of administration, a portion of the solution, typically approximately half, may be administered in the evening prior to an elective diagnostic, therapeutic, or surgical procedure, and the remainder of the solution on the day of surgery.

PL 216 059 B1

A formulation comprising ascorbic acid and a salt of ascorbic acid for use in the process of the invention has the advantageous characteristics of the formulation of the invention described above containing the corresponding ascorbic acid and a salt of ascorbic acid.

The present invention further relates to the use of PEG in the manufacture of a medicament for purging the colon of a mammal according to an administration regimen comprising the steps of:

a) administering 0.5 to 3.0 liters of colon cleansing solution containing PEG (volume VPEG) over a period of time t1 l

b) feeding 0.3 to 2.0 liters of clear fluid (volume Vcf) over a period of time t2.

The invention also relates to a method of cleansing the colon of a mammal, comprising orally administering to the mammal in the following steps:

a) 0.5 to 3.0 liters of a cleaning solution containing PEG (volume VPEG) over time period t1 i

b) 0.3 to 2.0 liters of clear fluid (volume Vcf) over a period of time t2.

t1 is preferably up to 2 hours, more preferably up to 1 hour 30 minutes, typically approximately one hour. t1 is preferably greater than 15 minutes, more preferably greater than 30 minutes. Similarly, t2 is preferably up to 2 hours, more preferably up to 1 hour 30 minutes, typically approximately one hour. t2 is preferably greater than 15 minutes, more preferably greater than 30 minutes.

Preferably, the VPEG is 500 ml or more, more preferably, the VPEG is 800 ml or more. Preferably, the VPEG is 2000 ml or less, more preferably, the VPEG is 1500 ml or less. For example, VPEG is approximately 1000 ml. Preferably, Vcf is 300 ml or greater, more preferably, 400 ml or greater. Preferably, Vcf is 1500 ml or less, preferably 1000 ml or less. For example, Vcf is approximately

500 ml. In practice, under medical supervision in a clinic, the clear liquid can be administered until the excretion of clear faeces free of any solids.

Using the inventive regimen, it has surprisingly been found that the weight of the resulting stool is greater than the usual cleansing regimen in which only the colon cleansing solution is administered. The present invention is the start of a new standard in which the use of hypertonic solutions containing PEG together with added electrolytes means that patients will have to drink additional water to produce an orthostatic flushing effect. After taking a significantly reduced volume of active solution, you can drink whatever liquid the patient chooses, including water, lemonade, and more.

As assumed by the Applicant, the total osmotic load after ingestion is important in determining the effectiveness of colon cleansing. By using the regimen according to the invention, it is possible to obtain the required osmotic load in a shorter period of time, which makes the start of the purification faster.

The use of a clarifying fluid allows the progress of colon cleansing, including completion, to be assessed by observing the excreted faeces. When the excreted feces are clear, there is no need for the patient to consume more fluid. The clear fluid can be any fluid that allows observation of the faeces being discharged. Typically the clear fluid is a water based drink including, for example, water, lemonade, cola, fruit syrups, clear fruit juices, and even clear alcoholic beverages such as beer. It is desirable that the clear fluid contains no significant or no fiber as this interferes with the colon cleansing process of the present invention. Accordingly, fruit juices such as orange juice and kiwi fruit juice and fruit juice drinks should be strained before use. Usually clear drinks based on fruit syrups, e.g. lime syrup, are suitable. Due to the desirability of excluding drinks containing glucose in order to reduce the risk of the formation of hydrogen or methane explosive gases in the intestines, "diet" drinks with little or no sugar are particularly suitable, e.g. drinks for diabetics, diet cola, diet lemonade, diet drinks carbonated or dietetic fruit syrups.

In general, the larger the volume of cleansing solution is administered, the greater the amount of stool. As previously described with reference to the prior art, 4 liters of colon cleansing solution is generally administered over 3 to 4 hours. Colon cleansing solutions generally have an unpleasant taste and many patients have difficulty ingesting the large amount of solution typically recommended. In accordance with another aspect of the present invention, it has been found that highly effective colon cleansing can be accomplished by first administering the cleansing solution in a smaller volume than is used in the art, followed by administering a clarifying fluid.

PL 216 059 B1

Suitable colon cleansing solutions for use in this method include, in particular, the colon cleansing solutions of the present invention described above.

Patient compliance is improved because the volume of cleansing solution that needs to be ingested is less than that used in the art. Compared to the consumption of a cleansing solution with a volume (VPEG + Vcf) but containing the same total amount of the ingredients of the composition, the efficacy, surprisingly, is not reduced. Water alone is not active as a cleansing solution. It is normally only absorbed in the gut.

Preferably, the colon is cleaned prior to diagnostic, therapeutic or surgical treatment of the colon, rectum or anus, or other abdominal part. The diagnostic or surgical procedure may be, for example, colonoscopy, contrast rectal enema, sigmoid colonoscopy, or colon surgery.

An embodiment of the two-step embodiment of the invention is the use of PEG in the manufacture of a medicament for purging a patient's colon according to an administration regimen comprising the steps of:

a) administering 0.5 to 3.0 liters of a first colon cleansing solution containing PEG (volume VPEG) over time period t1,

b) feeding 0.3 to 2.0 liters of clear fluid (volume Vcf) over a period of time t2, i

c) administering 0.5 to 3.0 liters of a second colon cleansing solution containing PEG (V2PEG volume) over a period of time t3.

The present invention also relates to a method of cleansing a patient's colon according to an administration regimen comprising the steps of:

a) administering 0.5 to 3.0 liters of a first colon cleansing solution containing PEG (volume VPEG) over time period t1,

b) feeding 0.3 to 2.0 liters of clear fluid (volume Vcf) over a period of time t2, i

c) administering 0.5 to 3.0 liters of a second colon cleansing solution containing PEG (V2PEG volume) over a period of time t3.

It has been found that efficacy and patient compliance is further improved when the colon cleansing solution is administered in two doses separated by the administration of water, compared to the administration of a single cumulative volume dose (i.e. VPEG + V2PEG).

Preferably, the VPEG is 500 ml or more, more preferably, the VPEG is 800 ml or more. Preferably, the VPEG is 2000 ml or less, more preferably, the VPEG is 1500 ml or less. For example, VPEG is approximately 1000 ml. Preferably, the V2PEG is 500 ml or more, more preferably, the V2PEG is 800 ml or more. Preferably, the V2PEG is 2000 ml or less, more preferably, the V2PEG is 1500 ml or less. For example, V2PEG is approximately 1000 ml. Preferably, Vcf is 300 ml or greater, more preferably, 400 ml or greater. Preferably, Vcf is 1500 ml or less, preferably 1000 ml or less. For example, Vcf is approximately 500 ml.

t1 is preferably 15 minutes or more, more preferably 30 minutes or more. t1 is preferably 2 hours or less, more preferably 1 hour 30 minutes or less. Typically t1 is approximately one hour. Likewise, t2 is preferably 15 minutes or more, more preferably 30 minutes or more. t2 is preferably 2 hours or less, more preferably 1 hour 30 minutes or less. Typically t2 is approximately one hour. t3 is preferably 15 minutes or more, more preferably 30 minutes or more. t3 is preferably 2 hours or less, more preferably 1 hour 30 minutes or less. Typically t3 is approximately one hour.

Preferably, administration of the second dose of colon cleansing solution is followed by administration of a second dose of clarifying fluid (V2cf) over a period of time t4. Preferably, V2cf is 500 ml or more, more preferably, 800 ml or more. Preferably, V2cf is 2000 ml or less, preferably 1500 ml or less. For example, V2cf is approximately 1000 ml. In practice, under medical supervision in a clinic, the clear liquid can be administered until the excreted feces are clear and contain no solids. t4 is preferably 30 minutes or more, more preferably 1 hour or more. t4 is preferably 3 hours or less, more preferably 2 hours 30 minutes or less. Typically t4 is approximately two hours.

The volume of the resulting stool increases significantly after introducing the clearing fluid administration steps of the present invention. It is much easier for the patient to accept this treatment. Of the nine volunteers, eight were more responsive to administering the cleansing solution in two doses separated by water than administering the cleansing solution in a single larger dose.

PL 216 059 B1

Suitable colon cleansing compositions for use in the method of the invention include in particular the compositions of the invention described above.

The composition may be in the form of two or more components. For example, the first component may be a composition for making a first PEG-containing colon cleansing solution and the second component a composition for making up a second PEG-containing colon cleansing solution. Preferably, one or both of the components comprises ascorbic acid and / or a salt thereof. The two components are preferably in unit dosage form, for example a composition in a sachet or other suitable container. In such a system, the ascorbic acid and / or its salts are preferably packaged separately from the other ingredients. For example, the first sachet may contain polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, sweeteners and flavors, and the second sachet may contain ascorbic acid and sodium ascorbate, both of which are used to prepare a first colon cleansing solution. A third sachet containing polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, sweeteners and flavors, and a fourth sachet containing ascorbic acid and sodium ascorbate may be attached, both of which are used to prepare a second colon cleansing solution.

The various two or more component delivery systems of the compositions of the invention will generally contain the desired composition in a unit dosage form. A unit dose generally corresponds to an amount of dry composition suitable for constitution with water. The volume may be any, e.g. suitable for use in the two-step or multi-step administration regimen described above, each unit dose may be appropriate to prepare the entire volume of a solution for use in one of the specified purification steps. Alternatively, the unit dose may be appropriate to prepare a defined volume, e.g., liter of cleansing solution.

A convenient form of the medicament for the patient is a dry composition in a kit, e.g., in a box, containing the composition and instructions for its use. The composition is preferably in unit dosage form (s) as described above.

The present invention also relates to the use of a solution containing ascorbic acid and / or one or more of its salts, an alkali metal or alkaline earth metal sulfate, a relatively large amount of PEG and, optionally, additional electrolytes for the treatment of patients with constipation, intestinal gas, symptoms of recurrent spasms or perianal irritation. PEG is ingested in an amount of 200 g or more per day, preferably more than 200 g per day, preferably more than 300 g per day, in divided doses. It may be in solid form which, after suspension in an aqueous medium, is administered from 1 to 4 times a day, preferably from 1 to 2 times a day. The number of administrations per day depends on the severity of the constipation.

Phase III clinical trials conducted to compare the efficacy, safety and patient acceptance of the composition of the present invention (NRL994) with the polyethylene glycol + electrolyte (PEG + E) KleanPrep® (also known as GoLYTELY) solution and with sodium phosphate solution (NaP, also known as as FLEETS) show an effectiveness equal to that of PEG + E and NaP compositions, see Example 6.

Moreover, the composition of the invention was better accepted than PEG + E, with better taste and lower volume ingested being taken into account. Moreover, NRL994 has been shown to be as safe as PEG + E in a group of patients with increased risk factors (hospitalized patients). Moreover, a comparison with NaP showed a better safety profile for the compositions of the invention without clinically significant changes or disturbances in electrolytes. In summary, the composition of the invention provides effective and safe bowel cleansing with patient compliance equivalent to the use of NaP. Moreover, the composition of the invention does not require restriction of its use in younger and healthier patients undergoing routine colonoscopy as required by NaP.

Accordingly, the composition of the present invention can be used to treat a patient population for whom it would be inappropriate or unsafe to use PEG + E or, particularly, NaP; e.g. in an outpatient setting, in very young and elderly patients, and in patients for whom the use of NaP, in particular, is excluded.

Examples

P r z k ł a d 1

Comparison of the effectiveness of 2-liter solutions of Movicol, Movicol + ascorbic acid and Movicol + ascorbic acid + sodium sulfate

Healthy volunteers were given a 2-liter dose of each of the following formulations of A) Movicol, B) Movicol + ascorbic acid and C) Movicol + ascorbic acid + sodium sulfate, and the volume of the resulting stool was measured. Movicol is a registered trade name of Norgine Limited used for the product listed in Table 2 below. A double-blind crossover study was performed with 2 dosing periods with Formulas A and B. Each volunteer was given formulation A and formulation B once in random order. Neither the volunteers nor the medical staff in charge knew which preparation was given first. For formulation C, a third, open study period was introduced. The composition of Movicol is shown in Table 2. The compositions of the three formulations are shown in Table 3.

T a b l i c a 2: Composition of Movicol per liter

Ingredient Quantity Macrogol 3350 (PEG) 105 g Sodium bicarbonate 1.428 g Sodium chloride 2.805 g Potassium chloride 0.373 g Lime-lemon flavor * 0.800 g

* Flavor SN292403 Lemon / Limona Nat. Trusil J2076 available from International Flavors and Fragrances (IFF)

T a b l i c a 3:

Composition of preparations A, B and C per liter

Relationship Preparation A Preparation B Preparation C Movicol 1x 1x 1x Sucrose (vitamin C placebo) 10 g 0 0 Ascorbic acid 0 10 g 10 g Sodium sulfate 0 0 5.6 g Osmolarity: mOsmoli / l 200 228 346

The osmolarity values given in Table 3 are values calculated based on the formulation composition. The calculated osmolarity of Movicol is 171 mOsmol / l. The calculations assume that the polyethylene glycol does not contain any ionic impurities, and the pH is assumed to be such that the ascorbic acid is substantially completely associated.

Formulation A contained sucrose to minimize flavor differences between the formulations. Ascorbic acid enhances the flavor of intestinal preparations.

Each volunteer was administered 2 liters of each formulation over two hours at a rate of 250 ml per 15 minutes. The stool was collected within eight hours after the start of the administration. The amount of stool produced is shown in Table 4.

T a b l i c a 4:

Results of comparative preparations of preparations

Parameter Preparation A Preparation B Preparation C Stool weight / g 1465.2 ± 56.7 1862 ± 140.8 2735 ± 199 Stool volume / l 1.4 ± 0.0 1.8 ± 0.1 2.7 ± 0.2 PEG weight in stool / g 192.6 ± 16.6 197.0 ± 10.9 177.0 6.8

PL 216 059 B1

T a b l i c a 5:

Statistical significance (p) of the preparation comparative experiments

Parameter C against A C against B B against A Stool weight / g <0.001 0.002 0.005 Stool volume / l <0.001 0.003 <0.001 PEG weight in stool / g 0.63 0.45 0.92

Tables 4 and 5 show that the addition of 10 g / L ascorbic acid to Movicol resulted in a statistically significant increase in stool weight and volume.

In addition, the addition of 10 g / L ascorbic acid and 5.6 g / L sodium sulfate to Movicol resulted in an even greater statistically significant increase in stool weight and volume. Administration of preparation C causes an almost twofold increase in the weight and volume of excreted stool in comparison with preparation A. Comparing the results obtained for preparations B and C, the weight and volume of the stool increased by approximately 50% (statistical significance p = 0.002 for the weight of the stool, p = 0.003 for stool volume).

Solutions containing ascorbic acid were well tolerated. Three volunteers experienced nausea while taking preparation A (without ascorbic acid), while only two volunteers experienced nausea while taking preparation B and only two volunteers experienced nausea while taking preparation C. Both solutions B and C were considered more palatable than solution A. Solution C was surprisingly found to be as palatable as solution B. Moreover, despite the fact that solution C was hypertonic, no adverse effects were found.

No other or more serious side effects were observed. After the intake of solutions containing ascorbic acid, a slight (statistically non-significant) increase in blood potassium level and a net increase in ascorbemia were recorded in volunteers.

Finally, the addition of 10 g / L ascorbic acid to Movicol resulted in a significant and statistically significant increase in stool weight and volume. Stool weight and volume further increased, in a statistically significant manner, upon adding 5.6 g / L of sodium sulfate to the Movicol / ascorbic acid composition. Accordingly, a solution containing Movicol, ascorbic acid and sodium sulfate proved to be the most effective cleansing solution, and the greater effectiveness was unexpectedly not accompanied by any side effects or taste deterioration.

Subsequent studies in which the properties of the compositions of the present invention were compared with those of the compositions currently in the market, also demonstrated that the compositions and methods of the present invention have surprisingly superior properties.

P r z k ł a d 2

Comparison of the compositions according to the invention

A study was conducted to evaluate the effect on the efficacy of the cleansing solutions of the invention by independently varying the amount of PEG, sodium sulfate, and the source of ascorbic acid. Six compositions were tested. The formulations were prepared as aqueous solutions of formulations A to F. The amount of each ingredient in formulations A to F per liter of formulation is indicated in Table 6.

T a b l i c a 6:

Compositions A to F of the Invention Ingredients are given in grams

Compo- an act PEG 3350 Sulfate sodium Acid ascorbic Ascorbate sodium NaCl KCl Osmolarity mOsmoli / l AND 100 7.5 0.0 0.0 2.691 1.058 308 B 100 7.5 5.0 0.0 2.691 1.058 337 C. 100 7.5 5.0 5.0 2.691 1.058 379 D 100 7.5 10.0 0.0 2.691 1.058 365 E. 100 5.0 5.0 5.0 2.691 0.819 329 F. 125 7.5 5.0 5.0 3.217 1.155 416

PL 216 059 B1

All compositions contained lemon flavor. Ungerer Lemon SDF lemon flavor obtained from RSSL Pharma.

Composition E (containing 100 g PEG, 5 g sodium sulfate, 5 g ascorbic acid, 5 g sodium ascorbate, electrolytes and flavor) was the reference composition in this study.

The volunteers were informed about the purposes and methods of the study, for which they gave their written consent. A medical history was taken from each volunteer and a physical examination was performed. 30 volunteers were selected. Each volunteer was randomly assigned two different treatment compositions so that a total of each composition was tested 10 times. Each composition was tested for one day, and two studies for each volunteer were separated by a "washout" period of 7 to 15 days.

Urine samples were collected from each volunteer the day before the clinical trial. Volunteers were advised to fast overnight prior to the study, and volunteers were scheduled to arrive at the clinic at 8:00 am. Each volunteer drank 2 liters of their assigned composition over a 2 hour period (two 125 ml glasses approximately every 15 minutes). Stool volume and weight were assessed from the start of fluid intake and during the next 8 hours. Volunteers were generally not allowed to eat during this study period, but those who felt thirsty and / or showed signs of dehydration were allowed to drink water 4 hours after the start of the study.

Weight, blood pressure and heart rate were measured before and 8 hours after the start of administration, or at any other time as determined by the treating physician. A blood sample was taken 4 hours after the start of the administration for analysis of electrolytes, urea, creatine, hematocrit and total protein in plasma. The second blood sample was frozen for later analysis of the amount of ascorbic acid. Urine was collected between the start of the administration and the end of this study period. The level of electrolytes was also assessed in the volume of urine collected on the day of the study. The second urine sample was frozen for later analysis of the amount of ascorbic acid.

The volunteers assessed the taste of the preparation immediately after taking all the recommended amount of the solution.

In the event of drop-out, non-compliance, or serious adverse events not related to the study, volunteers were substituted to obtain 30 compliant datasets. Similarly, if any of the volunteers required any medication during the study that could affect intestinal transport or interact with the study medication, they were also replaced by another volunteer. In total, 6 volunteers were replaced during the study.

Each volunteer was randomly administered one of the 6 compositions in the first experiment and another of the 6 compositions in the second experiment. Each volunteer therefore had its own control, which increased the credibility of the study. Each PEG composition had a similar appearance, and when dissolved in water, the volume and appearance of the composition were also similar. The compositions had a different flavor.

Most of the stool was passed 4 hours after the start of the study.

The results are the effectiveness of the compositions according to the invention

The volume and weight of the stools collected during the study are shown in Table 7.

T a b l i c a 7:

Total stool volume and weight

AND B C. D E. F. Volume (1) Average 1.926 2.249 2.613 2.510 2,195 2.555 SD 0.598 0.437 0.538 0.442 0.369 0.755 Range 0.65 - 2.62 1.58 - 2.84 1.80 - 3.40 1.44 - 3.08 1.49 - 2.60 1.17 - 3.50 Weight (g) Average 1992 2306 2684 2533 2283 2638 SD 625 437 567 442 381 745 Range 650 - 2744 1630 - 2920 1830 - 3557 1526 - 3150 1581 - 2765 1280 - 3513

The mean stool volume ranged between 1.9 and 2.6 liters.

As can be seen from Table 7, the mean stool volumes for the six compositions ranged between 1.9 and 2.6 liters. Taking the mean values into account, for compositions D, F and C, the resulting stool volumes were greater than for compositions B and E, for which the resulting stool volumes were greater than for composition A. standard deviation 443 ml) and consequently the overall comparison of the compositions to each other was not statistically significant (p <0.217). Similar results were obtained for stool weight

PL 216 059 B1 (p <0.318). Four individual volunteers (one for each of procedures A, B, C, and F) did not strictly follow the protocol. In the case of composition B and composition F, while taking in one of the volunteers developed mild vomiting, and in the case of compositions A and C, one of _three subjects received a reduced amount of solution of the composition (1,000 cm ^3, respectively 3 and 1500 cm ^3). When the results were analyzed excluding these procedures, the statistical interpretation was unchanged.

The time taken for the volunteers to ingest the test solutions was recorded and the results are shown in Table 8.

T a b l i c a 8:

Time of taking the preparation

AND B C. D E. F. Time (minutes) Average 112.8 ± 7.5 115.7 ± 15.6 117.8 + 16.7 116.7 ± 9.3 114.9 + 11.2 116.5 ± 13.3 ± SD 100 - 120 90 - 140 95 - 145 100 - 135 100 - 130 90 - 140 Range

There was no correlation between the time of ingestion and the volume of stools (r = -0.125 p <0.340).

Volunteers were asked to rate the salty, sour and sweet taste of the solutions on a scale of 0 to 3 where 0 = very pleasant, 1 = neutral, 2 = acceptable and 3 = unacceptable.

The taste evaluation results are shown in Table 9.

T a b l i c a 9: Results of the taste evaluation

AND B C. D E. F. Salty Average ± SD 2.6 + 0.5 2.6 ± 0.5 2.4 ± 0.5 2.1 ± 0.6 2.1 ± 0.4 2.1 ± 0.4 Range 2 - 3 2 - 3 2 - 3 1 - 3 1 - 3 2 - 3 Sour Average ± SD 1.4 ± 0.7 2.0 ± 0.5 1.6 ± 0.5 1.9 ± 0.7 1.8 ± 0.4 1.8 ± 0.4 Range 0 - 2 1 - 3 1 - 2 1 - 3 1 - 2 1 - 2 Sweet Average ± SD 2.1 ± 0.6 2.1 ± 0.4 2.1 ± 0.6 2.3 ± 0.7 2.1 ± 0 2.1 ± 0.6 Range 1 - 3 2 - 3 1 - 3 1 - 3 2 - 2 1 - 3

There was no significant difference between the solutions for salty (p <0.459) or sweet (P <0.238) taste. However, the sour taste assessment of the different solutions varied significantly (p <0.039), with composition A being the least acidic and composition B being the most acidic. The evaluation of Composition A was as expected since this composition did not contain an ascorbic acid source.

In terms of efficacy, there were no overall statistically significant differences between the compositions. This was due to the high degree of volatility. However, the addition of 10 g ascorbic acid (ascorbic acid or a mixture of ascorbic acid and sodium ascorbate) gave the best results. Thus, it was found that compositions C and D were the most effective solutions.

Assessment of laboratory test results

The stools were analyzed for ion content. The results for Composition D are shown in Table 10.

T a b l i c a 10:

Stool ionogram results for Composition D.

Ionogram (mmoles / liter) Ionogram (mmoles) 1 2 3 Na + N 10 10 Mean ± SD 109.6 276.6 ± 59.4 Range 97 - 122 148.3 - 375.8

Table 10 continues

1 2 3 K + N 10 10 Mean ± SD 14.9 ± 4.1 36.8 ± 12.2 Range 8 - 25 24.6 - 64.3 er N 10 10 Mean ± SD 26.8 6.8 68.2 ± 25.8 Range 19 - 42 36.0 - 129.4

There were no statistically significant differences between the ionograms for the six different procedures. The hematocrit percentage was measured before and after the test and the results for composition D are shown in Table 11.

T a b l i c a 11:

Percentage of hematocrit before and after testing for composition D.

% Hematocrit Before N 10 Mean ± SD 42.1 ± 4.4 Range 31.7 - 46.0 After N 8 Mean ± SD 43.3 ± 5.6 Range 29.8 - 48.3. Difference N 9 Mean ± SD 1.47 ± 0.52

Multiple comparisons between the hematocrit percentages for the various compositions revealed no statistically significant differences. Similar results were obtained for compositions A, B, C, E and F.

Blood concentrations of sodium, potassium, chloride and bicarbonate were measured before and after administration of the composition. The results are shown in Tables 12, 13, 14 and 15.

T a b l i c a 12:

Change in blood sodium concentration (mmole / L)

AND B C. D E. F. Before N 10 10 9 10 9 10 Mean ± SD 141.0 ± 1.4 140.4 ± 1.2 140.8 ± 1.6 141.7 ± 2.0 140.7 ± 2.4 140.9 ± 2.5 Range 139 - 143 139 - 142 139 - 143 139 - 145 137 - 144 137 - 145 After N 10 10 10 10 10 10 Mean ± SD 143.5 ± 2.3 142.5 ± 2.5 143.8 ± 1.2 143.6 ± 2.3 143.7 ± 2.1 145.4 ± 2.2 Range 139 - 148 137 - 146 142 - 146 140 - 146 140 - 147 141 - 148 Difference N 10 10 9 10 9 10 Mean ± SD 2.5 ± 0.79 2.1 ± 0.89 3.22 ± 0.66 1.9 ± 0.59 2.86 ± 1.09 4.5 + 0.78

As can be seen from Table 12, a borderline significant difference was observed between compositions B and C (p = 0.053). A statistically significant difference was found between compositions B and F (p = 0.016) and between compositions E and F (p = 0.039). Administration of composition F resulted in the greatest increase in blood sodium levels.

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T a b l i c a 13:

Change in blood potassium (mmole / L)

AND B C. D E. F. Before N 10 10 9 10 9 10 Mean ± SD 4.1 ± 0.4 4.0 ± 0.2 4.0 ± 0.2 4.0 ± 0.3 4.1 ± 0.2 3.9 ± 0.2 Range 3.5 - 4.5 3.7 - 4.3 3.7 - 4.5 3.4 - 4.5 3.7 - 4.4 3.5 - 4.2 After N 10 10 10 10 10 10 Mean ± SD 4.1 ± 0.4 4.4 ± 0.3 4.5 ± 0.3 4.6 ± 0.2 4.2 ± 0.4 4.3 ± 0.3 Range 3.3 - 4.6 4.0 - 4.9 4.0 - 5.0 4.2 - 4.9 3.5 - 5.0 3.9 - 4.8 Difference N 10 10 9 10 9 10 Mean ± SD 0.08 ± 0.09 0.41 ± 0.11 0.51 ± 0.10 0.61 ± 0.13 0.19 ± 0.14 0.43 ± 0.07

Multiple comparisons showed no significant differences between the compositions.

T a b l i c a 14:

Change in blood chloride concentration (mmole / L)

AND B C. D E. F. Before N 10 10 9 10 9 10 Mean ± SD 102.3 ± 1.6 101.4 ± 2.5 102.1 ± 1.4 102.5 ± 2.3 102.3 ± 1.7 103.3 ± 2.6 Range 100 - 105 98 - 105 100 - 104 100 - 107 100 - 105 100 - 107 After N 10 10 10 10 10 10 Mean ± SD 105.6 ± 1.8 106.2 ± 3.2 106.4 ± 2.4 107.4 ± 2.4 105.7 ± 1.5 108.9 ± 3.3 Range 103 - 108 102 - 112 104 - 112 104 - 111 104 - 108 105 - 114 Difference N 10 10 9 10 9 10 Mean + SD 3.3 ± 0.80 4.8 ± 0.87 4.44 ± 0.80 4.9 ± 0.41 3.22 ± 0.62 5.6 ± 0.69

As can be seen from Table 14, a borderline significant difference was observed between compositions A and D (p = 0.056). A statistically significant difference was observed between compositions A and F (p = 0.010), compositions B and F (p = 1.036), compositions D and E (p = 0.031) and compositions E and F (p = 0.005). Administration of composition F caused the greatest increase in blood chloride concentration.

T a b l i c a 15:

Change in blood bicarbonate concentration (mmole / L)

AND B C. D E. F. Before N 10 10 9 10 9 10 Mean ± SD 26.9 ± 3.3 28.2 ± 2.0 28.6 ± 2.1 28.9 ± 2.0 28.4 ± 2.1 26.3 ± 3.2 Range 19 - 30 25 - 31 26 - 32 26 - 32 25 - 32 20 - 31 After N 10 10 10 10 10 10 Mean ± SD 26.7 ± 3.3 26.1 ± 2.1 26.6 ± 1.9 25.5 ± 1.8 26.1 ± 2.2 25.6 ± 2.5 Range 25 - 29 24 - 31 24 - 30 22 - 27 22 - 30 23 - 31 Difference N 10 10 9 10 9 10 Mean + SD -0.2 ± 0.80 -2.1 ± 0.82 -1.78 ± 0.60 -3.4 ± 0.60 -1.89 ± 0.72 -0.7 ± 0.75

Multiple comparisons showed a significant difference between compositions A and D (p = 0.010) and between compositions E and F (p = 0.035)

Blood urea, creatinemia and proteinemia were measured. The results for Composition D are shown in Table 16.

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T a b l i c a 16:

Change in blood urea, creatinemia and proteinemia for composition D.

Urea (mmoles / l) Creatinemia (mmoles / liter) Proteinemia (g / l) Before N 10 10 10 Mean ± SD 4.9 ± 0.9 81.4 ± 11.9 75.3 ± 4.8 Range 3.6 - 6.3 64 - 98 69 - 83 After N 10 10 10 Mean ± SD 4.5 ± 1.0 80.9 ± 13.6 78.9 ± 5.8 Range 2.6 - 5.8 59 - 98 70 - 87 Difference N 10 10 10 Mean ± SD -0.39 ± 0.21 -0.50 ± 1.66 3.60 ± 1.77

Multiple comparisons between the compositions showed no significant differences. Similar results were obtained for compositions A, B, C, E and F.

Covariance analysis of differences for all biological parameters showed no significant results.

The urine was also analyzed for sodium, potassium and chloride. The results for the group of volunteers given Composition D are shown in Table 17.

T a b l i c a 17:

Modification of sodium, potassium and chloride in urine for composition D.

Sodium content (mmoles) Potassium content (mmoles) Chloride content (mmoles) Before N 10 10 9 Mean ± SD 63.6 ± 33.8 38.9 ± 21.3 69.8 ± 34.6 Range 23.5 - 105.0 7.8 - 69.0 19.7 - 112.0 After N 10 10 10 Mean ± SD 46.6 ± 47.1 24.8 ± 20.8 53.7 ± 48.4 Range 3.1 - 161.6 4.9 - 64.8 6.8 - 164.8

Slight, statistically non-significant, reductions in sodium, potassium and chloride levels in urine were observed. There were no statistically significant differences between the groups of test compositions. Similar results were obtained for compositions A, B, C, E and F.

Ascorburia was also measured and the results are shown in Tables 18 and 19.

Table 18: Askorburia ^A mole / liter)

AND B C. D E. F. N 8 8 7 7 4 4 Average 445.3 5266.9 7292.1 8408.6 8046.3 2556.5 SD 668.3 4402.9 1781.4 9641.3 2437.7 3690.4 Range 17-1756 158 - 15141 4913 - 9463 129 - 28390 4482 - 9835 338 - 8043

T a b l i c a 19: Askorburia ^ mole)

AND B C. D E. F. N 8 8 7 7 4 4 Average 154.3 1690.1 2631.3 2152.1 2423.6 1141.2 SD 223.0 1473.1 1134.9 1856.4 1406.1 1818.1 Range 2.5 - 527 47 - 4845 103 - 4216 77 - 5678 448 - 3740 108 - 3861

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There were no significant differences between the ascorbic compositions either in μmol / liter or μmol (pc 0.303 and pc 0.641, respectively). As expected composition A had the lowest level of ascorbic acid as the solution contained neither ascorbic acid nor its sodium salts.

Overall, all biochemical changes were not clinically significant and all compositions were clinically and biologically well tolerated.

Conclusions of the experiments carried out with the compositions according to the invention:

T a b l i c a 20:

Summary of the results for compositions A to F

Compo- an act Ingredient (g) Osmolarity mOsmole / l Average stool volume l Average decrease HCO3 mmoles / l PEG 3350 sulfate sodium acid ascorbic ascorbate sodium AND 100 7.5 0.0 0.0 308 1.9 0.2 B 100 7.5 5.0 0.0 337 2.2 2.1 C. 100 7.5 5.0 5.0 379 2.6 1.8 D 100 7.5 10.0 0.0 365 2.5 3.4 E. 100 5.0 5.0 5.0 329 2.2 1.9 F. 125 7.5 5.0 5.0 416 2.6 0.7

As can be seen from the data shown in Table 20, the stool volume was greater after administration of compositions containing 7.5 g of sodium sulfate (A, B, C, D and F) than that of a composition containing only 5 g of sodium sulfate (E). There was no significant difference between the equivalent solutions containing 100 g of polyethylene glycol (C) and 125 g of polyethylene glycol (F). After administration of compositions containing ascorbic acid and / or sodium ascorbate (B, C, D, E, and F), the stool volumes were greater than those of the compositions without ascorbic acid or sodium ascorbate (A). After administration of compositions containing 10 g ascorbic acid (D) or 5 g ascorbic acid with 5 g sodium ascorbate (C, E and F), the stool volume was greater than that of compositions containing 5 g ascorbic acid alone (B). The preparation containing 100 g of polyethylene glycol, 7.5 g of sodium sulphate and 10 g of ascorbic acid caused a clinically significant decrease in the level of bicarbonate in the plasma (D). This decrease was not observed for a composition containing 100 g of polyethylene glycol, 7.5 g of sodium sulfate, 5 g of ascorbic acid and 5 g of sodium ascorbate (C).

Weight loss for all volunteers was approximately 1 kg despite the reduced urine volume (200-300 ml in 8 hours). Proteinemia and hematocrit have increased, resulting in slight dehydration. Also natremia and kaliemia increased slightly. The concentration of polyethylene glycol in the stool was analyzed only in treatment groups D and F. Stool volumes correlated roughly with the amount of PEG measured in the collected stool.

P r z k ł a d 3

Investigation of the effect of water administration between consecutive administrations of colon cleansing compositions

Ten volunteers were selected for the study, who gave their written consent before the start of the study. Each volunteer was given 2 liters of Composition D with the composition as defined in Example 2. The composition was administered in two different ways at two different times separated by a washout period. In the first mode of administration (1), the volunteer drank 2 liters of composition D in 2 hours as in Example 2. In the second mode of administration (2), the volunteer drank 1 liter of the composition in 1 hour, then 500 ml of water in the next hour. followed by a second liter of composition in the next hour, and finally 1000 ml of water in the next 2 hours.

The stool was collected 8 hours after the start of the administration. A comparison of the stool weights for the two types of administration is shown in Table 21.

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T a b l i c a 21:

Stool weight comparison depending on the method of administration

Method 1 Way 2 Weight (g) N * 9 9 Average 2464 2726 SD 409 198 Range 1526 - 2865 2350 - 2920

* Number of volunteers

The volume of the stool produced after administration of Composition D was approximately 300 ml larger after using Method 2 compared to method 1. Volunteers were asked to rate the acceptance level of the administration methods on the Visual Analog Scale VAS, where 0 mm = the highest level. acceptance and 100mm = no acceptance, the results are shown in table 22.

T a b l i c a 22:

Comparison of the VAS acceptance level of methods of administration

Method 1 Way 2 VAS (mm) N 9 9 Mean ± SD 68.4 20.0 59.4 ± 21.0 Range 35 - 98 17 - 85

A statistically significant reduction (p <0.0276) of 10 mm on the VAS scale was observed in favor of a higher level of acceptance for mode 2 of administration. Of the nine volunteers, eight indicated the second route of administration as preferred.

P r z k ł a d 4

To evaluate the efficacy and safety of colon cleansing solution in patients undergoing colonoscopy, patients (12 male, 18 female, mean age 51 +/- 11) were given 2 liters of colon cleansing composition containing the ingredients listed in Table 23 per liter of solution.

T a b l i c a 23:

Colonoscopy after administration of the colon cleansing solution

Ingredient Weight (g) per l preparation PEG 3350 100.0 Sodium sulfate 7.5 Ascorbic acid 4.7 Sodium ascorbate 5.9 Sodium chloride 2.69 Potassium chloride 0.93 Lemon flavor 2.015 Anhydrous citric acid 1.565 Acesulfame K. 0.35 Calculated Osmolarity 392 mOsmoli / l

Colon cleansing solution was administered according to the following regimen: First hour: 1 liter of solution orally Second hour: 0.5 liters of water orally Third hour: 1 liter of solution orally

Fourth hour: at least 0.5 liters of water orally over 1.5 hours

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Colon cleansing assessed by colonoscopy on a 4 point scale (very good for all colon segments = grade 4, good for all colon segments = grade 3, at least one colon segment contains a fully or partially removable residue = grade 2 or 1, at least one colon segment contains hard, compact stool = grade 0). The results were then ranked A for Grade 3 or 4, B for Grade 1 or 2, and C for Grade 0. The investigating physician rated the quality of colon preparation as very good or good in 20 patients, moderate in at least one section in 6, bad in 3 and very bad for 1, which is reflected in the final score of 20A, 9B and 1C.

The mean stool weight was 2,866 +/- 667 g and the mean colon fluid volume removed during colonoscopy was 130 +/- 124 ml. The digestive tolerance of the preparation was good in 26 patients, moderate in 2 and poor also in 2. Only one patient experienced profuse vomiting. No statistically significant changes in blood concentrations of chloride or bicarbonate during the administration period were observed.

P r z k ł a d 5

Examples of preparations

Flavored preparation 1

T a b l i c a 23:

Composition of the preparation from UNGERER LEMON

Ingredient % by weight Weight (g) for 125 ml of the preparation Movicol Base 96.275 13.7008 Acesulfame K. 0.321 0.0455 Talin 0.058 0.0082 NHDC 0.058 0.0082 Citric acid 0.078 0.0110 Natrosol 250 M. 1,840 0.2606 Lemon flavor 0.920 0.1303

Talin is a thaumatin containing flavor enhancer (available from The Talin Food Company, Merseyide, England). NHDC (neohesperidine dihydrochloride) is a sweetener (available from Evesa, P.O. Box 103, 11300 La Linea de la concepcion, Cadiz, Spain). Natrosol 250 M is a hydroxyethyl cellulose available from Hercules Incorporated via Aqualon.

Flavored preparation 2

T a b l i c a 24:

Composition of the preparation from UNGERER STRAWBERRY

Ingredient % by weight Weight (g) for 125 ml of the preparation Movicol Base 97.603 13.7008 Acesulfame K. 0.325 0.0456 NHDC 0.014 0.0020 Natrosol 250 M. 1.858 0.2608 Strawberry flavor 1,800 0.2527

Flavored preparation 3

T a b l i c a 25:

Composition of the preparation with IFF Grapefruit Flavoring

Ingredient % by weight Weight (g) per 2 l of the preparation 1 2 3 PEG 3350 79.24 200.0 Sodium sulfate 5.94 15.0

Table 25 continues

1 2 3 Ascorbic acid 3.96 10.0 Sodium ascorbate 3.96 10.0 Sodium chloride 2.13 5.38 Potassium chloride 0.84 2.12 IFF Grapefruit Flavoring 2.41 6.08 Powder Anhydrous citric acid 1.23 3.10 Acesulfame K. 0.28 0.70 Calculated Osmolarity 392 mOsmoli / l 392 mOsmoli / l

Flavored preparation 4

T a b l i c a 26:

Composition of the preparation from UNGERER BLACKCURRANT

Ingredient % by weight Weight (g) per 2 l of the preparation PEG 3350 79.81 200.0 Sodium sulfate 5.99 15.0 Ascorbic acid 3.99 10.0 Sodium ascorbate 3.99 10.0 Sodium chloride 2.15 5.38 Potassium chloride 0.85 2.12 Currant flavor 1.62 4.06 Anhydrous citric acid 1.24 3.10 Acesulfame K. 0.28 0.70 Talin 0.08 0.20 Calculated Osmolarity 392 mOsmoli / l 392 mOsmoli / l

Flavored product 5

T a b l i c a 27:

Composition of the preparation with IFF Pineapple Flavoring

Ingredient % by weight Weight (g) per 2 l of the preparation PEG 3350 79.81 200.0 Sodium sulfate 5.99 15.0 Ascorbic acid 3.99 10.0 Sodium ascorbate 3.99 10.0 Sodium chloride 2.15 5.38 Potassium chloride 0.85 2.12 IFF Pineapple Flavoring Powder 1.70 4.06 Citric acid Anhydrous 1.26 3.10 Acesulfame K. 0.29 0.70 Calculated Osmolarity 392 mOsmoli / l 392 mOsmoli / l

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Flavored preparation 6

T a b l i c a 28:

Composition of the preparation with IFF Vanilla + Givaudan-Roure Lemon and Limona Flav-o-lok

Ingredient % by weight Weight (g) per 2 l of the preparation PEG 3350 78.95 200.0 Sodium sulfate 5.92 15.0 Ascorbic acid 3.95 10.0 Sodium ascorbate 3.95 10.0 Sodium chloride 2.12 5.38 Potassium chloride 0.84 2.12 IFF Vanilla Flavoring Powder 1.61 4.07 Givaudan-Roure Lemon and Limona Flav-o-lock 1.15 2.91 Anhydrous citric acid 1.22 3.09 Acesulfame K. 0.29 0.70 Calculated Osmolarity 392 mOsmoli / l 392 mOsmoli / l

In the following examples, ascorbic acid and sodium ascorbate are packaged separately from the rest of the ingredients to increase their stability.

a) Composition containing citric acid

The composition is in the form of two sachets. The contents of the two sachets together are used to prepare one liter of colon cleansing solution after adding water.

Sachet 1

PEG 3350: 100,000 g Sodium sulfate: 7,500 g Sodium chloride: 2.691 g Potassium chloride: 0.930 g Anhydrous citric acid: 1.565 g Acesulfame K: 0.350 g Lemon flavor: 2.015 g Total Weight of Sachet Ingredients 1 115.051 g Sachet 2 Ascorbic acid: 4.700 g Sodium Ascorbate: 5.900 g

Total weight in a sachet of 2 components 10.600 g

b) A composition containing as part

The composition is in the form of two sachets. The contents of the two sachets together are used to prepare after adding one liter of colon cleansing solution.

1 sachet (in grams per liter) PEG 3350: 100,000 g Sodium sulfate: 7,500 g Sodium chloride: 2.691 g Potassium chloride: 1.015 g Aspartame: 0.233 g Acesulfame K: 0.117 g Lemon flavor (Ungerer V3938-1N1) 0.340 g Total Weight of Sachet Ingredients 1 111.896 g

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2 sachet (in grams per liter)

Ascorbic acid: 4,700 g

Sodium ascorbate: 5.900 g

Total weight of the components of sachet 2 10.600 g

Comparative examples

Various attempts have been made to reduce the volume of prior art solutions in order to obtain a satisfactory colon cleansing. Relaxing agents, e.g. bisacodyl, picosulfate, or senna were added to the GoLYTELY solution. These provided effective bowel cleansing but increased the risk of disturbance of plasma electrolyte levels. In another trial, it was found that the highly concentrated GoLYTELY solution (only one liter was prepared from the powder for two one-liter doses) was effective at cleansing the intestines, but the solution was unpalatable, i.e. the participants found the taste of the solution so unpleasant that it was very difficult to consume the solution. Without direct medical supervision, such an unpleasant taste would likely lead the patient to refrain from taking the solution.

Example 6: Clinical trials

Two Phase III clinical trials were conducted to demonstrate the safety of polyethylene glycol + electrolytes (PEG + E) compositions and the level of patient acceptance of equivalent sodium phosphate solutions, both of which are currently used for bowel cleansing prior to colonoscopy.

Clinical examination 1

Research center (research centers):

Multicenter clinical trial involving a total of 12 specialist gastroenterology units in Germany.

Objectives:

Demonstration that NRL994 Oral Cleansing Solution (see below) is no less effective than the current standard treatment (PEG + E, Klean-Prep®, see below) on the overall quality of the enteric preparation in patients prescribed for colonoscopy.

Methodology:

The study was conducted as a randomized, drug-controlled, multicentre, equivational, single-blind phase III study with two parallel treatment groups. The patients were hospitalized and the selection for the study was one or two days before the planned endoscopy procedure. Both test products were administered in two equally divided doses; bowel cleansing was started the evening before surgery by administering the first half of the cleansing solution; and continued the next morning on the day of colonoscopy with the second half of the dose. The patient's participation in the study ended after the endoscopy was completed.

Number of volunteers:

362 hospitalized patients were selected for the study, with the recommendation of a complete colonoscopy.

Diagnosis and inclusion criteria:

Written consent male or female patients, 18 to 85 years of age, recommended for colonoscopy, no history of colon surgery, no contraindications for colonoscopy or treatment with NRL994.

Test product NRL994, dose, method of administration

Test product: One dose of NRL994 consisted of 100 g PEG 3350, 7.5 g sodium sulfate, 4.7 g ascorbic acid, 5.9 g sodium ascorbate, 46 mmol sodium chloride and 12.46 mmol potassium chloride. The product contained lemon flavor (2.015 g), anhydrous citric acid (1.565 g) and potassium acesulfame (0.35 g). (The product was the same as used in Example 4, see table 23.) One dose of powder had to be diluted with 1000 ml of water.

Total dose: two doses, one dose each (2 liters in total).

Methodology: Each one-liter dose of NRL994 was to be consumed within one hour and then washed down with 500 ml of additional clear liquid.

Duration of administration:

NRL994 was taken in two 1-liter divided doses separated by a night break: the first dose was to be taken in the afternoon or evening before surgery (until 22:00) and the second dose in the morning on the day of colonoscopy (starting at 06:00). In between ending

A break of at least one hour was required before starting a colonoscopy.

Reference treatment, dose, method of administration:

Reference product: PEG + E (Klean-Prep®) consisted of 59 g of PEG 3350, 5.7 g of sodium sulphate, 1.5 g of sodium chloride, 0.7 g of potassium chloride and 1.7 g of sodium bicarbonate. The product contained a vanilla flavor and a sweetener. One dose in the form of a powder had to be diluted with 1000 ml of water.

Total dose: four 1-liter doses (4 liters in total)

Methodology: One liter dose was to be consumed within one hour (250 ml per 15 minutes).

Duration of administration:

Four doses of PEG + E (Klean-Prep®) were also taken in divided and separated overnight rest: two doses (2 liters) were given in the afternoon or evening before surgery (until 22:00) and then two doses (2 liters) on the morning of the colonoscopy colon starting at 05:00. An interval of at least one hour was required between stopping treatment and starting colonoscopy.

Drugs administered in combination:

Co-administration of other products known to have a bowel cleansing effect (bowel irrigation solutions, potent laxatives, enemas) was excluded.

Conformity assessment:

Patients were instructed in detail on how to prepare and use NRL994 or PEG + E (Klean-Prep®) formulations; in most cases it was taken under a nursing supervision. In addition, patient compliance was assessed by comparing the number of sachets dispensed with the number of used sachets. The volumes of NRL994 or PEG + E (Klean-Prep®) solutions consumed and any remaining amounts were recorded by all patients.

Assessment criteria:

Timetable:

Day-2 or Day-1: eligibility assessment, basic medical and laboratory tests;

Day-1: in the evening, start of administration of enteric preparation (first dose of NRL994 or first two doses of PEG + E [Klean-Prep®]);

Day 0: In the morning, end intestinal preparation (second dose of NRL994 or last two doses of PEG + E [Klean-Prep®]), followed by colonoscopy at least one hour after the end of the last dose.

Efficacy evaluation criteria:

The primary efficacy criterion was the overall quality of the intestinal cleansing preparation as assessed by an independent panel of gastroenterology experts based on video cassettes recorded during colonoscopy without the experts knowing which drug was administered. Other endpoints were the degree of cleansing of individual bowel segments, overall quality of colon cleansing as assessed by a local endoscopic specialist, general use of the bowel lavage solution, and overall ease of colonoscopy. The level of patient acceptance was determined based on the following parameters recorded in the patient's card: taste assessment, overall taste assessment, patient satisfaction level, overall patient comfort and compliance with respect to volume intake and dietary restrictions. In addition, safety and tolerability were assessed.

Statistical methods:

The primary objective of the study was to demonstrate that the colon cleansing effect of a small volume of NRL994 is not inferior to that of a large volume of standard intestinal cleansing solution (PEG + E). NRL994 would be non-essential if the lower bound of the one-tailed 97.5% confidence interval of the difference in efficacy values between the two treatment groups did not exceed -15%.

A protocol analysis (PPA) and a treatment intent analysis (ITT) were performed. While the first was based solely on the assessment of an independent panel of experts, in the second, the missing results of the panel of experts were replaced by the assessment of the doctor performing a colonoscopy; patients for whom no assessment was available were treated as treatment failures. In addition, a modified treatment-based analysis (mITT) was performed, using a different treatment compliance definition for the patients assigned to this dataset.

A baseline efficacy analysis was performed from the protocol population and using efficacy values calculated by an independent panel of experts.

PL 216 059 B1

Parametric data was analyzed with the usual standard statistical data (mean, SD, median, minimum, maximum); frequency tables were calculated for categorical data.

Results submit:

This study was a study of the equivalence of the efficacy parameter (bowel cleansing). A total of 362 patients were selected for the study. Two patients completed the study prior to randomization and administration of study drug. One other patient was excluded after randomization due to allergy to the vanilla flavor in PEG + E. A total of 359 patients (NRL994: n = 180 and PEG + E: n = 179) received at least some study medication (ITT population). The mean age of the patients enrolled in the study was approximately 60 years (NRL994: 58.0 ± 16.0 years). The ITT and PP analyzes showed colon cleansing equal to NRL994 versus PEG + E, with a colon cleansing efficiency value of 88.9% for NRL994 versus 94.8% for PEG + E. Overall, the efficacy results show that taking the low volume (2 liters) of NRL994 is clinically as effective (+ 15%) as the high volume (4 liters) PEG + E formulation, which is considered the gold standard. Patients clearly and statistically significantly preferred NRL994 to PEG + E, based on the evaluation of several parameters of the level of patient acceptance, including taste and volume ingested. NRL994 was as safe as PEG + E and was generally well tolerated. No serious side effects were observed. The most frequently observed adverse reactions were treatment-related malaise, nausea, abdominal pain and vomiting. No differences were observed between the NRL994 and PEG + E formulations.

Overall, NRL994 is as effective and safe as PEG + E and, importantly, is easier to accept by patients because of the smaller volume ingested.

Clinical Study 2:

Researchers: 17 hospital endoscopy specialists; 4 experts selected from among 17 researchers.

Research center (research centers): 17 specialized hospital units for endoscopic examinations located in France.

Objectives: To evaluate the non-inferiority of efficacy and to compare the safety of NRL994 with NaP solution for colon cleansing prior to colonoscopy.

Methodology: Randomized, multicentre, drug-controlled, single-blind study (for the treating physician) with two parallel study groups, and additionally blinded for the primary efficacy parameter evaluator.

Number of patients: 181 male, 171 female, 352 in total.

Diagnosis and inclusion criteria:

Outpatient and inpatient male or female patients, 18 to 75 years of age, who gave written consent to the examination, for diagnostic or therapeutic colonoscopy.

Exclusion criteria: age <18 or> 75 years, illeus, suspected bowel obstruction or perforation, acquired or congenital colon dilatation, history of colon resection, Crohn's disease or ulcerative colitis, congestive heart failure NYHA III or IV, documented renal failure with creatinine > 170 micromol / L, known hypersensitivity to polyethylene glycols or Na phosphate and / or vitamin C, known G6PD deficiency, phenylketonuria, concurrent or within 90 days before the start of the study, participation in an experimental drug trial, pregnant women or women planning to become pregnant, women at the age of who do not use reliable methods of contraception, a disease or condition that the investigators believe may pose a significant risk to the patient may affect the results of the study or may significantly complicate the study.

PL 216 059 B1

Test product, dose, method of administration:

Test product: NRL994 (see above).

Total dose: Two doses of NRL994 each with a volume of 1 liter (total 2 liters).

Methodology: Each liter was to be drunk within 1 hour. In addition, after taking 2 liters of NRL994, one had to drink at least 1000 ml (or more) of any additional clear liquid except milk.

Reference treatment, dose, method of administration:

Reference product: NaP solution (Fleet Phospho Soda®)

Dose and methodology: The preparation (1 package) consisted of 2 bottles, each 45 ml. Each bottle contained 21.6 g of monobasic sodium phosphate monohydrate with 8.1 g of sodium phosphate dibasic heptahydrate in a buffered aqueous solution. The contents of each bottle had to be dissolved in 125 ml of water. Each intake of NaP solution was preceded and ended with 250 ml (or more if necessary) of a clear drink (not milk). There was a delay of at least 12 hours between the intake of the two 45 ml doses of NaP solution. In addition, an additional 750 ml of clear liquid (not milk) or more, if necessary, was to be drunk between the two administrations.

Duration of administration:

Both procedures were performed the day before colonoscopy surgery.

Assessment criteria:

The primary endpoint was overall bowel cleansing quality as assessed by an endoscopy specialist selected from a panel of evaluating physicians who did not know the name of the drug under consideration, based on video cassettes recorded during colonoscopy. Other efficacy endpoints were the overall quality of the bowel cleansing and the overall judgment of the local endoscopy specialist. The level of patient acceptance was determined on the basis of the following parameters recorded in the patient's card: overall patient satisfaction with the enteric preparation, the volume consumed, the ease of drinking the bowel lavage solution, adherence to dietary restrictions, declaration of drinking the same enteric preparation again and taste. In addition, safety and tolerability were assessed.

Statistical analysis: As in clinical trial 1.

Results submit:

This study is a test for the equivalence of the efficacy parameter (bowel cleansing). In total, 352 patients were selected for the study. Six patients from each group were excluded from all analyzes. A total of 340 patients (NRL994: n = 169 and NaP: n = 171) received at least some study drug (ITT population for safety). The mean age of enrolled patients was approximately 53 years for both groups. The ITT and PP analyzes showed the colon cleansing equivalence of NRL994 and NaP with a colon cleansing efficiency value of 72.5% for NRL994 compared to 63.9% for NaP (observed benefit for NRL994 compared to NaP was + 8.6%) . Overall, the efficacy results show that an intake of 2 liters of NRL994 is clinically equivalent to using a NaP solution.

The acceptance level parameters for NRL994 enteric preparation demonstrate significant advantages over NaP in terms of better taste, effect on individual activity, dietary adherence and willingness to reuse the same enteric preparation. NaP was beneficial in terms of patient compliance and ease of drinking the enteric formulation solution.

No serious adverse events were observed for the NRL994 group, but there were two cases of clinically significant hypocalcaemia in the NaP group. The number of patients with at least one study-related adverse event was significantly greater in the NaP group (11.1% of patients) compared to the NRL994 group (3.0%). In particular, a significant number of cases of hyperphosphataemia and hypocalcaemia were reported in the NaP group, indicating a risk for sensitive patients excluded from the study due to the known risks of NaP administration.

Overall, NRL994 is as effective as NaP, but is significantly more beneficial to patient comfort and safety than NaP.

Conclusions:

Both phase III studies demonstrate the efficacy of NRL994 equal to the solutions based on polyethylene glycol electrolytes (PEG + E) or sodium phosphate (NaP), which are often used in current clinical practice. Moreover, the preparation of NRL994 was better tolerated than PEG + E, being higher

Acceptance level was related to better taste and smaller intake volume. Moreover, NRL994 proved to be as safe as PEG + E in the group of patients with increased risk factors (hospitalized patients). In addition, a comparison with NaP showed a more favorable safety profile of NRL994 without clinically significant electrolyte changes or disturbances. Overall, NRL994 allows for an effective and safe bowel cleansing procedure with patient compliance equivalent to the use of NaP. In addition, NRL994 does not require restrictions on use in younger and healthier patients undergoing routine colonoscopy as required for NaP.

Claims (48)

A dry composition for mixing with water, characterized in that it contains the following ingredients per liter of aqueous solution of the composition: a) 80 to 150 g of polyethylene glycol (PEG), b) 3 to 20 g of ascorbic acid, one or more salts of ascorbic acid or a mixture of ascorbic acid and one or more salts of ascorbic acid, c) 1 to 15 g of alkali metal or alkaline earth metal sulphate or a mixture of alkali metal sulphates or alkaline earth metal sulphates and d) optionally, one or more electrolytes selected from the group consisting of sodium chloride, potassium chloride and sodium bicarbonate, wherein the components of the composition are selected such that 1 liter of prepared aqueous solution of the composition has an osmolarity in the range of 300 to 700 mOsmol / L (300 to 700 mol m ^-3 ). 2. A dry composition according to claim 1, The method of claim 1, wherein the aqueous solution has an osmolarity of 330 mOsmol / L (300 mol m ^-3 ) or greater. 3. A dry composition according to claim 1, The method of claim 1 or 2, wherein the aqueous solution has an osmolarity in the range of 550 mOsmol / l (550 mol m ^-3 ) or less. 4. A dry composition according to claim 1, The composition of claim 1, wherein the polyethylene glycol has an average molecular weight of 2,000 daltons or more. 5. A dry composition according to claim 1, The process of claim 1, wherein the polyethylene glycol has an average molecular weight of 4,500 or less. 6. A dry composition according to claim 1, The composition of claim 1, wherein the polyethylene glycol has an average molecular weight of 3,350 or 4,000. 7. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises 90 g or more of polyethylene glycol (PEG) per liter. 8. A dry composition according to claim 1, The composition of claim 1, wherein the composition contains 125 g or less of polyethylene glycol (PEG) per liter. 9. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises 100 g polyethylene glycol (PEG) per liter. 10. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises an alkali metal or alkaline earth metal sulphate or a mixture of alkali metal or alkaline earth metal sulphates in an amount of 3 g or more per liter. 11. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises an alkali metal or alkaline earth metal sulphate or a mixture of alkali metal or alkaline earth metal sulphates in an amount of 9 g or less per liter. 12. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises 7.5 g per liter of alkali metal or alkaline earth metal sulfate or a mixture of alkali metal or alkaline earth metal sulfates. 13. A dry composition according to claim 1, The method of claim 1, wherein the alkali metal or alkaline earth metal is magnesium. 14. A dry composition according to claim 1, The method of claim 1, wherein the alkali metal or alkaline earth metal is sodium. 15. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises sodium chloride. 16. A dry composition according to claim 16, The composition of claim 15, wherein the composition comprises sodium chloride in an amount of 2 g or more per liter. 17. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises potassium chloride. PL 216 059 B1 18. A dry composition according to claim 1, 17. The composition of claim 17, wherein the composition comprises potassium chloride in an amount of 0.5 g or more per liter. 19. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises ascorbic acid or a salt thereof in an amount of 5 g or more per liter. 20. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises ascorbic acid or a salt thereof in an amount of 15 g or less per liter. 21. A dry composition according to claim 1, The composition of claim 1, wherein the composition comprises ascorbic acid and a salt thereof. 22. A dry composition according to claim 22, The composition of claim 21, wherein the composition comprises ascorbic acid and its salt in a weight ratio ranging from 1: 9 to 9: 1. 23. A dry composition according to claim 1, The composition of claim 22, wherein the composition comprises ascorbic acid and its salt in a weight ratio ranging from 2: 8 to 8: 2. 24. A dry composition according to claim 24, The composition of claim 21, wherein the composition comprises ascorbic acid and its salt in a weight ratio ranging from 3: 7 to 7: 3. 25. A dry composition according to claim 1, The composition of claim 21, wherein the composition comprises ascorbic acid and its salt in a weight ratio ranging from 4: 6 to 6: 4. 26. A dry composition according to claim 1, The method of claim 1, wherein the ascorbic acid salt is an alkali metal salt or an alkaline earth metal salt. 27. A dry composition according to claim 27, The method of claim 26, wherein the salt of ascorbic acid is selected from the group consisting of sodium ascorbate, potassium ascorbate, magnesium ascorbate and calcium ascorbate. 28. A dry composition according to claim 28, The composition of claim 1, wherein the composition comprises sodium ascorbate. 29. A dry composition according to claim 1, The composition of claim 1, wherein the composition further comprises a flavor. 30. A dry composition according to claim 1, The composition of claim 29, wherein the flavor is lemon flavor. 31. A dry composition according to claim 1, The composition of claim 1, wherein the composition further comprises a sweetener which is not a substrate for the gut bacteria. 32. A dry composition according to claim 32, The method of claim 31, wherein the sweetener is selected from the group consisting of aspartame, acesulfame K, saccharin or a mixture thereof. 33. A dry composition according to claim 33. 31 wherein citric acid is present. 34. A dry composition according to claim 34, The method of claim 1, wherein the ascorbic acid and / or the salt of ascorbic acid are coated. 35. A dry composition according to claim 35; The method of claim 1, characterized in that per liter of the aqueous solution prepared therefrom, it contains 90 to 125 g of polyethylene glycol PEG 3350 or PEG 4000. 36. A dry composition according to claim 1, The method of claim 1, characterized in that per liter of the aqueous solution prepared therefrom, it contains 5 to 15 g of an ascorbate component containing ascorbic acid and sodium ascorbate in a weight ratio of 3: 7 to 7: 3. 37. A dry composition according to claim 1, The method of claim 1, characterized in that per liter of the aqueous solution prepared therefrom, it contains 5 to 10 g of sodium sulphate. 38. A dry composition according to claim 38, 2. A method according to claim 1, characterized in that per liter of the aqueous solution prepared therefrom, it contains 2 to 4 g of sodium chloride. 39. A dry composition according to claim 1, 2. A method according to claim 1, characterized in that per liter of the aqueous solution prepared therefrom, it contains 0.7 to 1.3 g of potassium chloride. 40. A dry composition according to claim 1, 1, characterized in that it contains two sachets with the following composition: Sachet 1 PEG 3350 polyethylene glycol 100,000 g Sodium sulfate 7,500 g Sodium chloride 2.691 g Potassium chloride 1.015 g Aspartame 0.233 g PL 216 059 B1 Acesulfame K. 0.117 g Lemon flavor 0.340 g Sachet 2 Ascorbic acid 4.700 g Sodium ascorbate 5.900 g 41. A dry composition according to any one of claims 1-7. The composition of 1-40, characterized in that the composition is in a sachet. 42. A dry composition comprising 2 servings, characterized in that the first serving comprises a composition as defined in any one of claims 1 to 4, including: 1-40 for the preparation of a first colon cleansing solution containing polyethylene glycol (PEG). and the second portion is a composition as defined in any one of claims 1 to 5; 1-40 for the preparation of a second colon cleansing solution containing polyethylene glycol (PEG). 43. An aqueous solution of a dry composition as defined in any one of claims 1 to 3. 1-40. 44. The solution according to claim 44 43. The method of claim 43 for cleansing the colon of a mammal. 45. The solution according to claim 45 The method of claim 43 for use as a colon cleansing solution. 46. The solution according to claim 46 43, wherein the solution is administered orally. 47. Use of a dry composition as defined in any one of claims 1-7. 1-40 or a solution as defined in any one of claims 1-40 43-46 for the manufacture of a medicament for cleansing the colon of a mammal. 48. A kit comprising dry composition ingredients according to any one of claims 1-8. A process as claimed in any one of the preceding claims, characterized in that it comprises at least two parts, wherein the ascorbic acid and / or its salts are packed in the first part and the remaining ingredients are packed in the second part.